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Photosensitized destruction of human bladder carcinoma cells treated with chlorin e6-conjugated microspheres.

机译:二氢卟酚e6偶联微球处理的人膀胱癌细胞的光敏破坏。

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摘要

A photosensitizer conjugate, chlorin e6 (Ce6) covalently bound to 1-micron-diameter polystyrene microspheres, has been investigated in the photodynamic destruction of MGH-U1 human bladder carcinoma cells in vitro. The microspheres were taken up avidly by the carcinoma cells; confocal laser scanning fluorescence microscopy showed them to be localized in the cytoplasm, apparently within lysosomes, visualized by labeling with acridine orange. In contrast, fluorescence of unconjugated Ce6 was present within most cellular membranes. Use of Ce6-microsphere conjugates led to a 20-fold-higher mean intracellular concentration, compared with unconjugated Ce6. Cells incubated in the presence of Ce6-microsphere conjugates (0.43 microM equivalent) and subsequently irradiated at 659 nm with a dye laser pumped by an argon-ion laser showed dose-dependent phototoxicity, leading to total inhibition of colony formation at a radiant exposure of 5J/cm2; in contrast, cells incubated with either unconjugated Ce6 (0.43 microM) or unconjugated microspheres before laser irradiation were unaffected. Cells pretreated with Ce6-microsphere conjugates and irradiated in the presence of 90% 2H2O showed significantly increased phototoxicity, an effect consistent with an important role for excited-state singlet oxygen in the mechanism of injury. In solution, however, photosensitized generation of singlet oxygen with Ce6-microsphere conjugates was 9 times less efficient than with unconjugated Ce6. The markedly greater phototoxicity of Ce6-microsphere conjugates compared to unconjugated Ce6 was therefore a consequence of the high intracellular Ce6 concentration attained by phagocytosis of the conjugates and their particular sites of intracellular localization. Thus, these conjugates are an efficient system for the delivery of photosensitizing drugs to carcinoma cells.
机译:共价结合到1微米直径的聚苯乙烯微球的光敏剂共轭二氢卟酚e6(Ce6)已在体外MGH-U1人膀胱癌细胞的光动力破坏中进行了研究。微球被癌细胞强烈吸收;共聚焦激光扫描荧光显微术显示它们位于细胞质中,显然在溶酶体内,通过用a啶橙标记可见。相反,大多数细胞膜中都存在未结合的Ce6的荧光。与未缀合的Ce6相比,使用Ce6微球缀合物可导致平均细胞内浓度高20倍。在Ce6微球缀合物(0.43 microM当量)存在下孵育并随后用氩离子激光泵浦的染料激光在659 nm照射的细胞显示出剂量依赖性的光毒性,从而导致在辐射剂量下完全抑制菌落形成。 5J /平方厘米;相反,在激光辐照之前,用未结合的Ce6(0.43 microM)或未结合的微球孵育的细胞不受影响。用Ce6-microsphere偶联物预处理并在90%2H2O存在下照射的细胞显示出显着增加的光毒性,这一作用与激发态单线态氧在损伤机理中的重要作用相一致。然而,在溶液中,Ce6-微球共轭物光敏产生单线态氧的效率比未共轭Ce6的效率低9倍。因此,与未缀合的Ce6相比,Ce6-微球缀合物的光毒性显着更大,这是由于缀合物的吞噬作用及其特定的胞内定位位点所导致的高细胞内Ce6浓度的结果。因此,这些缀合物是用于将光敏药物递送至癌细胞的有效系统。

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